Guo Zhong, Li Sha, Lv Meng, Liu Zonghua, Xue Wei
Key Laboratory of Biomaterials of Guangdong Higher Education Institutes, Department of Biomedical Engineering, and §Institute of Life and Health Engineering, Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Jinan University, Guangzhou, 510632, China.
Key Laboratory of Biomaterials of Guangdong Higher Education Institutes, Department of Biomedical Engineering, and Institute of Life and Health Engineering, Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Jinan University, Guangzhou, 510632, China.
ACS Biomater Sci Eng. 2017 Oct 9;3(10):2420-2430. doi: 10.1021/acsbiomaterials.7b00538. Epub 2017 Sep 20.
Polycations such as polyethylenimine and chitosan have been widely used as mucosal vaccine delivery systems due to their permeation enhancement effect. Preferably, environmentally responding biodegradable polycations would be better carrier materials for mucosal vaccine delivery. Disulfide bond-based redox-sensitive polycations could respond to the higher intracellular glutathione concentration and degrade in the cytoplasm via the breakage of the disulfide bonds, which are particularly suitable for antigen delivery. In this work, we evaluated the potential of redox-sensitive, biodegradable polycation poly(amido amine) (PAA) as mucosal vaccine carriers. From the primary studies with ovalbumin used as a model protein antigen, it is found that PAA could complex with and encapsulate protein antigen via electrostatic attraction, enhance the cellular uptake of antigen by dendritic cell line DC2.4, prolong antigen residence in nasal cavity, and promote antigen permeation into nasal submucosal layer. Further, Balb/c mice were intranasally immunized with PAA-delivered recombinant hemagglutinin (HA) antigen protein of H7N9 influenza virus. The PAA/HA formulations induced significantly more potent systemic IgG response and mucosal IgA response, higher splenocyte proliferation activity, higher secretion levels of cytokines IFN-γ and IL-4 by splenocytes, more memory CD4 and CD8 T cells, and more DCs expressing MHC II molecule. From the results, the redox-responsive polycation PAA as vaccine carriers helped elicit more potent cellular and humoral immune responses. Particularly, PAA induced much higher cellular immune response compared with previously reported carrier materials. The intelligent PAA could be developed as efficient mucosal vaccine delivery systems for clinical applications.
诸如聚乙烯亚胺和壳聚糖等聚阳离子，由于其渗透增强作用，已被广泛用作黏膜疫苗递送系统。更理想的是，对环境有响应的可生物降解聚阳离子将是更好的黏膜疫苗递送载体材料。基于二硫键的氧化还原敏感聚阳离子可对细胞内较高的谷胱甘肽浓度做出响应，并通过二硫键的断裂在细胞质中降解，这特别适合用于抗原递送。在这项工作中，我们评估了氧化还原敏感的可生物降解聚阳离子聚（酰胺胺）（PAA）作为黏膜疫苗载体的潜力。从以卵清蛋白作为模型蛋白抗原的初步研究中发现，PAA可通过静电吸引与蛋白抗原结合并包裹，增强树突状细胞系DC2.4对抗原的细胞摄取，延长抗原在鼻腔中的停留时间，并促进抗原渗透到鼻黏膜下层。此外，用PAA递送的H7N9流感病毒重组血凝素（HA）抗原蛋白对Balb/c小鼠进行鼻内免疫。PAA/HA制剂诱导出显著更强的全身IgG反应和黏膜IgA反应、更高的脾细胞增殖活性、脾细胞更高的细胞因子IFN-γ和IL-4分泌水平、更多的记忆性CD4和CD8 T细胞，以及更多表达MHC II分子的树突状细胞。从结果来看，作为疫苗载体的氧化还原响应性聚阳离子PAA有助于引发更强的细胞免疫和体液免疫反应。特别是，与先前报道的载体材料相比，PAA诱导出更高的细胞免疫反应。智能PAA可被开发为用于临床应用的高效黏膜疫苗递送系统。
